Process for the preparation of dipeptidylpeptidase inhibitors

ABSTRACT

The present invention provides a process for the preparation of linagliptin, a compound of Formula I, the process comprising deprotecting a compound of Formula II wherein R 1  and R 2  together with the nitrogen to which they are attached form a phthalimido group, wherein the aromatic ring of the phthalimido group is substituted with one or more R 3  substituents selected from the group consisting of halogen, alkyl, nitro and amino; or R 1  is H and R 2  is selected from the group consisting of trialkylsilyl,  2 -trialkylsilylethoxycarbamates, acetyl, trihaloacetyl,  9 -fluorenylmethoxycarbonyl, trityl, alkylsulfonyl, arylsulfonyl, diphenylphosphine and sulfonylethoxycarbonyl.

PRIORITY

This application claims the benefit under 35 U.S.C. §119 to IndianProvisional Application No. 2410/MUM/2012, filed on Aug. 17, 2012,3461/MUM/2012 filed on Dec. 7, 2012, U.S. Provisional Application No.61/710,548, filed on Oct. 5, 2012, the contents of which areincorporated by reference herein.

FIELD OF THE INVENTION

The present invention relates to a novel process for preparation ofdipeptidylpeptidase inhibitors. More specifically the present inventionrelates to novel compounds of 3-aminopiperidine derivatives and theiruse as possible intermediates in the preparation of dipeptidylpeptidaseinhibitors, like linagliptin and alogliptin.

BACKGROUND OF THE INVENTION

Inhibitors of dipeptidylpeptidase IV, also DPP-IV inhibitors orgliptins, are a class of oral hypoglycemics that block DPP-IV. They canbe used to treat diabetes mellitus type 2.

Linagliptin, which is chemically known as8-[3(R)-Aminopiperidin-1-yl]-7-(2-butynyl)-3-methyl-1-(4-methylquinazolin-2-ylmethyl)xanthine,is represented by compound of Formula I.

TRADJENTA® is Boheringer's (R)-linagliptin 5 mg once daily tabletindicated for type 2 diabetes mellitus as an adjunct to diet andexercise.

Alogliptin chemically known as2-[6-[3(R)-Aminopiperidin-1-yl]-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-ylmethyl]benzonitrileis represented by the structural formula, shown below

Alogliptin is a dipeptidylpeptidase IV (DPP4) inhibitor approved inJapan for monotherapy and in combination with an alpha-glucosidaseinhibitor for the once-daily, oral treatment of type 2 diabetes.

U.S. Pat. No. 7,407,955 (US Pat. '955) discloses linagliptin and processfor preparing it. US Pat. '955 discloses process for preparinglinagliptin by deprotecting N-BOC protected linagliptin.

Presently, we have developed a novel process for the preparation oflinagliptin which involves deprotecting a compound of Formula II.

wherein R₁ and R₂ together with the nitrogen to which they are attachedform a phthalimido group, wherein the aromatic ring of the phthalimidogroup is substituted with one or more R₃ substituents selected from thegroup consisting of halogen, alkyl, nitro and amino; or R₁ is H and R₂is selected from the group consisting of trialkylsilyl,2-trialkylsilylethoxycarbamates, acetyl, trihaloacetyl,9-fluorenylmethoxycarbonyl, trityl, alkylsulfonyl, arylsulfonyl,diphenylphosphine and sulfonylethoxycarbonyl.

The process of the present invention is novel, commercially advantageousand industrially feasible and leads to the formation of linagliptin inhigher yields and purity as compared to the known process.

SUMMARY OF THE INVENTION

The present invention provides a process for the preparation oflinagliptin, a compound of Formula I,

the process comprising deprotecting a compound of Formula II

wherein R₁ and R₂ together with the nitrogen to which they are attachedform a phthalimido group, wherein the aromatic ring of the phthalimidogroup is substituted with one or more R₃ substituents selected from thegroup consisting of halogen, alkyl, nitro and amino; or R₁ is H and R₂is selected from the group consisting of trialkylsilyl,2-trialkylsilylethoxycarbamates, acetyl, trihaloacetyl,9-fluorenylmethoxycarbonyl, trityl, alkylsulfonyl, arylsulfonyl,diphenylphosphine and sulfonylethoxycarbonyl.

The present invention provides a compound of Formula II

wherein R₁ and R₂ are as defined above.

The present invention provides a compound of Formula IV

wherein R₁ and R₂ together with the nitrogen to which they are attachedform a phthalimido group, wherein the aromatic ring of the phthalimidogroup is substituted with one or more R₃ substituents selected from thegroup consisting of halogen, alkyl, nitro and amino; or R₁ is H and R₂is selected from the group consisting of trialkylsilyl,2-trialkylsilylethoxycarbamates, acetyl, trihaloacetyl,9-fluorenylmethoxycarbonyl, trityl, alkylsulfonyl, arylsulfonyl,diphenylphosphine and sulfonylethoxycarbonyl.

The present invention provides a process for the preparation of acompound of Formula IVA

wherein the aromatic ring of the phthalimido group is substituted withone or more R₃ substituents selected from the group consisting ofhalogen, alkyl, nitro and amino; the process comprising reactingR-(3)-aminopiperidine with substituted phthalic anhydride wherein thearomatic ring of the phthalic anhydride is substituted with one or moreR₃ substituents selected from the group consisting of halogen, alkyl,nitro and amino.

The present invention provides Linagliptin dibenzoyl-D-tartaric acidsalt.

The present invention provides use of Linagliptin dibenzoyl-D-tartaricacid for the preparation of linagliptin.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1: is an X-ray powder diffraction pattern of compound ofLinagliptin dibenzoyl-D-tartaric acid salt.

FIG. 2: is Differential scanning calorimetry endotherm of Linagliptindibenzoyl-D-tartaric acid salt.

FIG. 3: is Thermogravimetric analysis curve of Linagliptindibenzoyl-D-tartaric acid salt.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a process for preparation of linagliptin,a compound of Formula I,

comprising deprotecting a compound of Formula II

wherein R₁ and R₂ together with the nitrogen to which they are attachedform a phthalimido group, wherein the aromatic ring of the phthalimidogroup is substituted with one or more R₃ substituents selected from thegroup consisting of halogen, alkyl, nitro and amino; or R₁ is H and R₂is selected from the group consisting of trialkylsilyl,2-trialkylsilylethoxycarbamates, acetyl, trihaloacetyl,9-fluorenylmethoxycarbonyl, trityl, alkylsulfonyl, arylsulfonyl,diphenylphosphine and sulfonylethoxycarbonyl.

The term “halogen” as used herein means iodine, bromine, chlorine andfluorine. The term “alkyl” as used herein includes a straight orbranched chain hydrocarbon containing from 1 to 6 carbon atoms.Representative examples of alkyl include, but are not limited to methyl,ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl,isopentyl, neopentyl, n-hexyl. The term “trialkylsilyl” as used hereinincludes trimethylsilyl, triethylsilyl and the like. The term“trihaloacetyl” as used herein includes trichloroacetyl, tribromoacetyl,trifluoroacetyl and the like. The term “alkylsulfonyl” as used hereinincludes methanesulfonyl, ethanesulfonyl and the like. The term“arylsulfonyl” as used herein includes benzenesulfonyl and tosyl and thelike.

The aromatic ring of the phthalimido group is substituted with one, two,or more R₃ substituents. The R₃ substituents may be present in anyposition of the aromatic ring. Preferably the R₃ substituent is an alkylgroup present at position 4 of the aromatic ring.

In one embodiment, the present invention provides a process for thepreparation of linagliptin, compound of Formula I, the processcomprising deprotecting a compound of Formula II wherein the linagliptinis obtained in a yield of at least 85%.

In one embodiment, the present invention provides a process for thepreparation of linagliptin, compound of Formula I, the processcomprising deprotecting a compound of Formula II wherein the linagliptinis obtained in a yield of at least 85% and/or a chemical purity of atleast 95% as determined by HPLC.

In one embodiment, the present invention provides a process for thepreparation of linagliptin, compound of Formula I, the processcomprising deprotecting a compound of Formula IIA, wherein the aromaticring of the phthalimido group is substituted with one or more R₃substituents selected from the group consisting of halogen, alkyl,nitro, amino.

The deprotection of compound of Formula II A may be carried out by usingreagents selected from the group consisting of hydrazine, hydrazinehydrate and amines.

The amines for deprotection may be selected from primary amine,secondary amine and tertiary amine which may be unsubstituted orsubstituted by small functional groups like hydroxy, nitro, halo.Preferably primary amines like methylamine, ethyl amine, ethanolamineare used for deprotection.

The deprotection reaction may be carried out in a solvent selected fromthe group consisting of alcohols, nitriles, hydrocarbons, halogenatedhydrocarbons, ether and water or mixtures thereof. The alcohol may beselected from the group consisting of methanol, ethanol, propanol,isopropanol, butanol, 2-butanol, isobutanol, pentanol and the like ormixtures thereof. The nitriles may be selected from the group consistingof acetonitrile, propionitrile and the like. The hydrocarbon may beselected from the group consisting of hexane, heptane, toluene, benzeneand the like. The halogenated hydrocarbon may be selected from the groupconsisting of methylene dichloride, ethylene dichloride and the like.The ethers may be selected from the group consisting of dioxane, diethylether, tetrahydrofuran, tetrahydropyran and the like.

In one embodiment, the present invention provides a process for thepreparation of linagliptin, compound of Formula I, the processcomprising deprotecting a compound of Formula IIA, wherein R₃ is alkyl.

In one embodiment, the present invention provides a process for thepreparation of linagliptin, compound of Formula I, the processcomprising deprotecting a compound of Formula IIA1.

In one embodiment, the present invention provides a process for thepreparation of linagliptin, compound of Formula I, the processcomprising deprotecting a compound of Formula IIA1 with ethanolaminewithout using additional solvent.

In one embodiment, the present invention provides a process for thepreparation of linagliptin, compound of Formula I, the processcomprising deprotecting a compound of Formula IIA1 with ethanolamine ina hydrocarbon solvent.

In one embodiment, the present invention provides a process for thepreparation of linagliptin, compound of Formula I, the processcomprising deprotecting a compound of Formula IIA1 with hydrazinehydrate in an alcoholic solvent.

In one embodiment, the present invention provides a process fordeprotecting a compound of Formula II, wherein R₁ is H and R₂ istrialkylsilyl or trialkylsilylethoxycarbamates, the process comprisingusing quaternary ammonium compounds such as tetrabutylammonium fluoridein the presence of solvents such as dimethylformamide, tetrahydrofuranand the like in mildly basic conditions.

In one embodiment, the present invention provides a process fordeprotecting a compound of Formula II, wherein R₁ is H and R₂ is acetyl,trihaloacetyl, alkylsulfonyl, arylsulfonyl, diphenylphosphine, theprocess comprising using an acid or a base.

The acids used for deprotection may be selected from mineral acids likehydrochloric acid, sulfuric acid, nitric acid or organic acids such asacetic acid, methanesulfonic acid, trichloroacetic acid, p-toluenesulfonic acid and the like.

The base used for deprotection may be selected from inorganic base ororganic base. The inorganic base may be selected from the groupconsisting of alkali metal hydroxides such as sodium hydroxide,potassium hydroxide, barium hydroxide and lithium hydroxide and thelike; metal carbonates such as sodium carbonate, potassium carbonate,magnesium carbonate, and calcium carbonate and the like; metalbicarbonates such as sodium bicarbonate, and potassium bicarbonate;metal hydrides such as lithium hydride, sodium hydride, and potassiumhydride and the like; borohydrides such as sodium borohydride, potassiumborohydride; and bases such as lithium aluminium hydride and ammonia.The organic base may be selected from the group consisting of organicamines such as triethylamine, diisopropylethylamine,N,N-dimethylaniline, pyridine, 4-dimethylaminopyridine,tri-n-butylamine, N-methylmorpholine, piperidine and the like; alkalimetal alkoxides such as sodium methoxide, sodium ethoxide,sodium-tert-butoxide, potassium methoxide, potassium ethoxide,potassium-tert-butoxide lithium methoxide, lithium ethoxide,lithium-tert-butoxide and the like.

In one embodiment, the present invention provides a process fordeprotecting a compound of Formula II wherein R₁ is H and R₂ is9-fluorenylmethoxycarbonyl, the process comprising using organic aminessuch as piperidine, morpholine, piperazine and the like.

In one embodiment, the present invention provides a process fordeprotecting a compound of Formula II wherein R₁ is H and R₂ is trityl,the process comprising using mild acids such as trifluoroacetic acid,trichloroacetic acid or by using 1-hydroxy-1-H benzotriazole. Thereaction may be carried out in solvent selected from halogenatedhydrocarbon or trifluoroethanol.

In one embodiment, the present invention provides a process fordeprotecting a compound of Formula II wherein R₁ is H and R₂ issulfonylethoxycarbonyl, the process comprising using inorganic bases asdescribed above.

In one embodiment, the present invention provides a compound of FormulaII

wherein R₁ and R₂ together with the nitrogen to which they are attachedform a phthalimido group, wherein the aromatic ring of the phthalimidogroup is substituted with one or more R₃ substituents selected from thegroup consisting of halogen, alkyl, nitro and amino; or R₁ is H and R₂is selected from the group consisting of trialkylsilyl,2-trialkylsilylethoxycarbamates, acetyl, trihaloacetyl,9-fluorenylmethoxycarbonyl, trityl, alkylsulfonyl, arylsulfonyl,diphenylphosphine and sulfonylethoxycarbonyl.

In one embodiment, the present invention provides a compound of FormulaIIA, wherein the aromatic ring of the phthalimido group is substitutedwith one or more R₃ substituents selected from the group consisting ofhalogen, alkyl, nitro, amino.

In one embodiment, the present invention provides a compound of FormulaIIA, wherein R₃ is alkyl.

The alkyl group may be selected from the group consisting of methyl,ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl,isopentyl, neopentyl, n-hexyl and the like and may be present at one ormore positions of the aromatic ring. Preferably the alkyl group ismethyl and it is present in the 4^(th) position of the aromatic ring.

In one preferred embodiment, the present invention provides a compoundof Formula IIA1.

In one embodiment, the present invention provides a compound of FormulaII, wherein R₁ is H and R₂ is acetyl, represented below.

In one embodiment, the present invention provides a compound of FormulaII, wherein R₁ is H and R₂ is trihaloacetyl, preferably trifluoroacetyl,represented below.

In one embodiment, the present invention provides a process, for thepreparation of a compound of Formula II

the process comprising reacting a compound of Formula III, wherein X isa halogen, with a compound of Formula IV;

wherein R₁ and R₂ together with the nitrogen to which they are attachedform a phthalimido group, wherein the aromatic ring of the phthalimidogroup is substituted with one or more R₃ substituents selected from thegroup consisting of halogen, alkyl, nitro and amino; or R₁ is H and R₂is selected from the group consisting of trialkylsilyl,2-trialkylsilylethoxycarbamates, acetyl, trihaloacetyl,9-fluorenylmethoxycarbonyl, trityl, alkylsulfonyl, arylsulfonyl,diphenylphosphine and. sulfonylethoxycarbonyl.

The reaction of compound of Formula III with compound of Formula IV maybe carried out in the presence of a base. The base may be selected froman organic base and an inorganic base. The inorganic base may beselected from the group consisting of alkali metal hydroxides such assodium hydroxide, potassium hydroxide, barium hydroxide and lithiumhydroxide and the like; metal carbonates such as sodium carbonate,potassium carbonate, magnesium carbonate, and calcium carbonate and thelike; metal bicarbonates such as sodium bicarbonate, and potassiumbicarbonate; metal hydrides such as lithium hydride, sodium hydride, andpotassium hydride and the like; borohydrides such as sodium borohydride,potassium borohydride; and bases such as lithium aluminium hydride andammonia. The organic base may be selected from the group consisting oforganic amines such as triethylamine, diisopropylethylamine,N,N-dimethylaniline, pyridine, 4-dimethylaminopyridine,tri-n-butylamine, N-methylmorpholine, piperidine and the like; alkalimetal alkoxides such as sodium methoxide, sodium ethoxide,sodium-tert-butoxide, potassium methoxide, potassium ethoxide,potassium-tert-butoxide lithium methoxide, lithium ethoxide,lithium-tert-butoxide and the like.

The reaction of compound of Formula III with compound of Formula IV maybe carried out in the presence of a solvent selected from the groupconsisting of alcohols, glycols, ethers, ketones, dimethylformamide,dimethylsulfoxide, sulfolane, N-methylpyrrolidone and the like.

The alcohol may be selected from the group consisting of methanol,ethanol, propanol, isopropanol, butanol, 2-butanol, isobutanol, pentanoland the like or mixtures thereof. The glycols may be selected fromethylene glycol, propylene glycol and the like. The ethers may beselected from the group consisting of dioxane, diethyl ether,tetrahydrofuran, tetrahydropyran, ethylenene glycol monomethylether,ethylene glycol diethylether and the like.

The reaction of compound of Formula III with compound of Formula IV maybe carried out at room temperature or reflux temperature of the solventused.

In one embodiment, the present invention provides a process for thepreparation of a compound of Formula IIA, wherein the aromatic ring ofthe phthalimido group is substituted with one or more R₃ substituentsselected from the group consisting of halogen, alkyl, nitro, amino, the

process comprising reacting a compound of Formula III, wherein X is ahalogen, with a compound of Formula IVA, wherein the aromatic ring ofthe phthalimido group is substituted with one or more substituentsselected from the group consisting of halogen, alkyl, nitro and amino.

In one embodiment, the present invention provides a process for thepreparation of a compound of Formula IIA, wherein R₃ is alkyl, theprocess comprising reacting a compound of Formula III, wherein X ishalogen with a compound of Formula IVA, wherein R₃ is alkyl.

In one preferred embodiment, the present invention provides a processfor the preparation of a compound of Formula IIA1, the

process comprising reacting a compound of Formula III, wherein X ishalogen with a compound of Formula IVA1

Preferably, X is bromine in the compound of Formula III and the reactionis carried out in the presence of dimethyl formamide and an inorganicbase such as potassium carbonate.

In one preferred embodiment, the present invention provides a processfor the preparation of a compound of Formula IIA1, the processcomprising reacting a compound of Formula III, wherein X is halogen witha compound of Formula IVA1 in N-methylpyrrolidone anddiisopropylethylamine.

The compound of formula IIA1 may be purified in a solvent selected fromalcohols or halogenated hydrocarbons or mixtures thereof.

In one embodiment the compound of formula IIA1 may be purified frommethanol.

In one embodiment the compound of formula IIA1 may be purified frommethanol and methylene dichloride.

The present invention provides a compound of Formula IV;

wherein R₁ and R₂ together with the nitrogen to which they are attachedform a phthalimido group, wherein the aromatic ring of the phthalimidogroup is substituted with one or more R₃ substituents selected from thegroup consisting of halogen, alkyl, nitro and amino; or R₁ is H and R₂is selected from the group consisting of trialkylsilyl,2-trialkylsilylethoxycarbamates, acetyl, trihaloacetyl,9-fluorenylmethoxycarbonyl, trityl, alkylsulfonyl, arylsulfonyl,diphenylphosphine and sulfonylethoxycarbonyl.

The present invention provides a compound of Formula IVA;

wherein the aromatic ring of the phthalimido group is substituted withone or more R₃ substituents selected from the group consisting ofhalogen, alkyl, nitro and amino.

The present invention provides a compound of Formula IVA, wherein R₃ isalkyl.

Specifically the present invention provides a compound of Formula IVA1

The present invention provides a process for the preparation of acompound of Formula IV;

wherein R₁ and R₂ together with the nitrogen to which they are attachedform a phthalimido group, wherein the aromatic ring of the phthalimidogroup is substituted with one or more R₃ substituents selected from thegroup consisting of halogen, alkyl, nitro and amino; or R₁ is H and R₂is selected from the group consisting of trialkylsilyl,2-trialkylsilylethoxycarbamates, acetyl, trihaloacetyl,9-fluorenylmethoxycarbonyl, trityl, alkylsulfonyl, arylsulfonyl,diphenylphosphine and sulfonylethoxycarbonyl; the process comprisingresolving a racemic compound of Formula V, wherein R₁ and R₂ are same asabove, with an optically active acid.

The present invention provides a process for the preparation of acompound of Formula IVA;

-   -   wherein the aromatic ring of the phthalimido group is        substituted with one or more R₃ substituents selected from the        group consisting of halogen, alkyl, nitro and amino; the process        comprising resolving a racemic compound of Formula VA,

with an optically active acid.

The present invention provides a process for the preparation of compoundof Formula IVA wherein R₃ is alkyl; the process comprising resolving aracemic compound of Formula VA, wherein R₃ is alkyl, with an opticallyactive acid.

In one embodiment, the present invention provides a process for thepreparation of a compound of Formula IVA1,

the process comprising resolving a racemic compound of Formula VA1, withan optically active acid

The optically active acid for resolution may be selected from the groupconsisting of S-(+) mandelic acid, R-(−) mandelic acid, L-(+)tartaricacid, D-(−)tartaric acid, L-malic acid, D-malic acid, D-maleic acid,(−)-naproxen, (+)-naproxen, (+)-ibuprofen; (−)ibuprofen,(IR)-(−)-camphor sulfonic acid, (IS)-(+)-camphor sulfonic acid,(IR)-(+)-bromocamphor-10-sulfonic acid,(IS)-(−)-bromocamphor-10-sulfonic acid, (−)-Dibenzoyl-L-tartaric acid,(−)-Dibenzoyl-L-tartaric acid monohydrate, (+)-Dibenzoyl-D-tartaric acidmonohydrate, (+)-dipara-tolyl-D-tartaric acid,(−)-dipara-tolyl-L-tartaric acid, L(−)-pyroglutamic acid,L(+)-pyroglutamic acid, (−)-lactic acid, L-lysine and D-lysine and thelike. Preferably the optically active acid is selected fromL-(+)tartaric acid, D-(−)tartaric acid, (−)-Dibenzoyl-L-tartaric acid,(−)-Dibenzoyl-L-tartaric acid, (+)-dipara-tolyl-D-tartaric acid,(−)-dipara-tolyl-L-tartaric acid.

In one embodiment, the present invention provides a process for thepreparation of a compound of Formula IVA1,

the process comprising

-   -   (a) treating a racemic compound of Formula VA1, with an        optically active acid to form a mixture of diasteromeric salts;    -   (b) separating the desired diasteromeric salt, a compound of        Formula VI, from the mixture of diasteromeric salts; and

-   -   (c) treating the compound of Formula VI with a base to obtain a        compound of Formula IVA1.

The term “OAA” in the compound of Formula VI is used to denote anoptically active acid.

The optically active acid may be selected from the acids discussedsupra. Preferably the optically active acid is selected, fromL-(+)tartaric acid, D-(−)tartaric acid, (−)-Dibenzoyl-L-tartaric acid,(−)-Dibenzoyl-L-tartaric acid, (+)-dipara-tolyl-D-tartaric acid,(−)-dipara-tolyl-L-tartaric acid.

The diastereomeric mixture of salts obtained by the reaction of aracemic compound of Formula VA1 with the optically active acid may beseparated based on differential solubility in solvents and the compoundof Formula IVA1 may be obtained by treating the separated diasteromericsalt of compound of Formula VI with a base.

The bases used may be selected from the group consisting of ammonia,hydroxides such as sodium hydroxide, potassium hydroxide, carbonatessuch as sodium carbonate, potassium carbonate, lithium carbonate,alkoxides such as potassium methoxide, sodium methoxide, tert-butoxide,and bicarbonates such as sodium bicarbonate, potassium bicarbonate.

The undesired enantiomer may be optionally racemized and again convertedto the desired enantiomer.

In one embodiment, the present invention provides a process for thepreparation of a compound of Formula IV, wherein R₁ is H and R₂ isselected from the group consisting of trialkylsilyl,2-trialkylsilylethoxycarbamates, acetyl, trihaloacetyl,9-fluorenylmethoxycarbonyl, trityl, alkylsulfonyl, arylsulfonyl,diphenylphosphine and sulfonylethoxycarbonyl,

the process comprising reacting R-(3)-aminopiperidine withtrialkylsilylamine, 2-trialkylsilylethoxy carbamate, trihaloacetamide,9-fluorenylmethoxycarbonyl derivative, trityl derivative,alkylsulfonamide, arylsulfonamide, diphenylphosphine derivative andsulfonylethoxycarbonyl derivative respectively.

In one embodiment, the present invention provides a process for thepreparation of compound of Formula IVA

wherein the aromatic ring of the phthalimido group is substituted withone or more R₃ substituents selected from the group consisting ofhalogen, alkyl, nitro and amino; the process comprising reactingR-(3)-aminopiperidine with substituted phthalic anhydride wherein thearomatic ring of the phthalic anhydride is substituted with one or moreR₃ substituents selected from the group consisting of halogen, alkyl,nitro and amino.

In one embodiment, the present invention provides a process for thepreparation of compound of Formula IVA1, the process comprising reactingR-(3)-aminopiperidine with 4-methylphthalic anhydride.

In another aspect, the present invention provides a process for thepreparation of compound of Formula IIA1

the process comprising reacting a compound of Formula III, wherein X ishalogen with a compound of Formula VI

The reaction of a compound of Formula III with a compound of Formula VImay be carried out in the presence of a base. The base may be selectedfrom an organic base and an inorganic base. The reaction of compound ofFormula III with compound of Formula VI may be carried out in thepresence of a solvent selected from the group consisting of alcohols,glycols, ethers, ketones, dimethylformamide, dimethylsulfoxide,sulfolane, N-methylpyrrolidone and the like.

The present invention provides the preparation of the starting compoundof Formula V, the process comprising reacting 3-aminopiperidine withsubstituted phthalic anhydride, trimethylsilylamine,2-trimethylsilylethoxy carbamate, trihaloacetamide,9-fluorenylmethoxycarbonyl derivative, trityl derivative,alkylsulfonamide, arylsulfonamide, diphenylphosphine derivative andsulfonylethoxycarbonyl derivative. The present invention provides thepreparation of the compound of Formula VA1, the process comprisingreacting 3-aminopiperidine with alkyl substituted phthalic anhydridespecifically the compound of Formula VA2 may be prepared by reacting3-aminopiperidine with 4-methyl phthalic anhydride.

In one embodiment, the present invention provides linagliptindibenzoyl-D-tartaric acid salt.

In one embodiment, the present invention provides crystallinelinagliptin dibenzoyl-D-tartaric acid salt.

In one embodiment, the present invention provides crystallinelinagliptin dibenzoyl-D-tartaric acid salt characterized by XRD patternas depicted in FIG. 1.

In one embodiment, the present invention provides crystallinelinagliptin dibenzoyl-D-tartaric acid salt characterized by XRD patternhaving peak reflections at about 6.35, 7.52, 14.05±0.2 degrees 2 theta.

In one embodiment, the present invention provides linagliptinditoluoyl-D-tartaric acid salt.

In one embodiment, the present invention provides use of Linagliptindibenzoyl-D-tartaric acid for the preparation of linagliptin.

In one embodiment, the present invention provides use of Linagliptindibenzoyl-D-tartaric acid for the preparation of linagliptin with achiral purity of at least 99.95% as determined by HPLC.

In one embodiment, the present invention provides a process forpreparing pure linagliptin comprising

-   -   a. converting the linagliptin into linagliptin        dibenzoyl-D-tartaric acid salt;    -   b. treating the linagliptin dibenzoyl-D-tartaric acid salt with        a suitable base to form linagliptin; and    -   c. isolating the pure linagliptin.

The reaction of linagliptin with dibenzoyl-D-tartaric acid to formlinagliptin dibenzoyl-D-tartaric acid salt may be carried out inalcoholic solvents such as methanol. If required the linagliptindibenzoyl-D-tartaric acid salt may be purified using isopropanol.

In one embodiment the linagliptin dibenzoyl-D-tartaric acid salt isconverted to linagliptin by treatment with an organic or inorganic basesuch as sodium hydroxide, potassium hydroxide and the like.

In one embodiment the present invention provides linagliptin havingchemical purity greater than 99.6% as determined by High performanceliquid chromatography (HPLC). In one embodiment the present inventionprovides linagliptin having compound of formula IIA1 less than 0.15% asdetermined by HPLC. In one embodiment the present invention provideslinagliptin having compound of formula III less than 0.15% as determinedby HPLC. In one embodiment the present invention provides linagliptinhaving compound of formula IVA1 less than 0.15% as determined by HPLC.

In one embodiment die present invention, provides linagliptin havingimpurity X observed in HPLC at relative retention time of 2.29 andhaving mass m/z value of 716 as characterized by mass spectrometry inless than 0.15% as determined by HPLC. Preferably less than 0.05%. Inone embodiment the present invention provides linagliptin substantiallyfree of impurity X.

HPLC methodology: Reagents, Solvents and Standards: Water (Milli Q orequivalent) Acetonitrile (HPLC grade), Sodium perchlorate (GR Grade)Perchloric acid (70%) (GR Grade) Chromatographic Conditions: Apparatus:A High Performance Liquid Chromatograph equipped with quaternarygradient pumps, variable wavelength UV (detector attached with datarecorder and integrator software. Column: Inertsil ODS 3V, 250×4.6 mm,Column temperature: 30° C. Sample Cooler temperature: 25° C. MobilePhase: Mobile Phase A=Buffer: Acetonitrile (80:20, v/v) Buffer: 0.01 MSodium perchlorate in water. Adjust pH 4.0 with 5% Perchloric acid inwater. Mobile Phase B=Buffer:Acetonitrile (20:80, v/v) Diluent:Buffer:Acetonitrile (1:1, v/v) Flow Rate: 1.0 mL/minute Detection: UV225 nm Injection Volume: 20 μL. The retention time of linagliptin isabout 9.2 minutes under these conditions. Relative retention time forimpurity X with respect to the main peak is 2.29.

In one embodiment the present invention provides linagliptin havingchiral purity greater than 99.98% as determined by HPLC.

In one embodiment the present invention provides linagliptin having achemical purity of at least 99.6% and chiral purity of 99.95% asdetermined by HPLC.

In one embodiment the present invention provides linagliptin havingchemical purity greater than 99.6% and chiral purity greater than 99.98%as determined by HPLC.

In one aspect, the present invention provides a process for thepreparation of alogliptin, the process comprising reacting a compound ofFormula VII wherein X is halogen, with a compound of Formula IVA1 toobtain compound of formula VIII, followed by deprotecting the compoundof Formula VIII.

In another embodiment, the present invention provides a polymorphicmixture, comprising at least about 0.5 weight %, based on the totalweight of the mixture, of polymorph Form A or polymorph Form B oflinagliptin, with the remaining amount of the mixture being the otherpolymorph form of linagliptin. In another embodiment, the presentinvention provides a polymorphic mixture, comprising at least about 1weight %, based on the total weight of the mixture, of polymorph Form Aor polymorph Form B of linagliptin, with the remaining amount of themixture being the other polymorph form of linagliptin. In anotherembodiment, the present invention provides a polymorphic mixture,comprising at least about 2.5 weight %, based on the total weight of themixture, of polymorph Form A or polymorph Form B of linagliptin, withthe remaining amount of the mixture being the other polymorph form oflinagliptin. In another embodiment, the present invention provides apolymorphic mixture, comprising at least about 5 weight %, based on thetotal weight of the mixture, of polymorph Form A or polymorph Form B oflinagliptin, with the remaining amount of the mixture being the otherpolymorph form of linagliptin. In yet another embodiment, the presentinvention provides a polymorphic mixture, comprising at least about 10weight %, based on the total weight of the mixture, of polymorph Form Aor polymorph Form B of linagliptin, with the remaining amount of themixture being the other polymorph form of linagliptin. In yet anotherembodiment, the present invention provides a polymorphic mixture,comprising at least about 15 weight, based on the total weight of themixture, of polymorph Form A or polymorph Form B of linagliptin, withthe remaining amount of the mixture being the other polymorph form oflinagliptin. In yet another embodiment, the present invention provides apolymorphic mixture, comprising at least about 20 weight %, based on thetotal weight of the mixture, of polymorph Form A or polymorph Form B oflinagliptin, with the remaining amount of the mixture being the otherpolymorph form of linagliptin. In yet another embodiment, the presentinvention provides a polymorphic mixture, comprising at least about 25weight %, based on the total weight of the mixture, of polymorph Form Aor polymorph Form B of linagliptin, with the remaining amount of themixture being the other polymorph form of linagliptin.

In yet another embodiment, the present invention provides a polymorphicmixture, comprising about 25 weight % to about 90 weight % of polymorphForm A of linagliptin and about 75 weight % to about 10 weight % ofpolymorph Form B of linagliptin. In yet another embodiment, the presentinvention provides a polymorphic mixture, comprising about 80 weight %(±5%) of polymorph Form A of linagliptin and about 20 weight % (±5%) ofpolymorph Form B of linagliptin. In yet another embodiment, the presentinvention provides a polymorphic mixture, comprising about 70 weight %(±5%) of polymorph Form A of linagliptin and about 30 weight % (±5%) ofpolymorph Form B of linagliptin. In yet another embodiment, the presentinvention provides a polymorphic mixture, comprising about 60 weight %(±5%) of polymorph Form A of linagliptin and about 40 weight % (±5%) ofpolymorph Form B of linagliptin. In yet another embodiment, the presentinvention provides a polymorphic mixture, comprising about 50 weight %(±5%) of polymorph Form A of linagliptin and about 50 weight % (±5%) ofpolymorph Form B of linagliptin. In yet another embodiment, the presentinvention provides a polymorphic mixture, comprising about 40 weight %(±5%) of polymorph Form A of linagliptin and about 60 weight % (±5%) ofpolymorph Form B of linagliptin. In yet another embodiment, the presentinvention provides a polymorphic mixture, comprising about 30 weight %(±5%) of polymorph Form A of linagliptin and about 70 weight % (±5%) ofpolymorph Form B of linagliptin. In yet another embodiment, the presentinvention provides a polymorphic mixture, comprising about 75% ofpolymorph Form A of linagliptin and about 25% of polymorph Form B oflinagliptin.

In yet another embodiment, the present invention provides a process forthe preparation of a polymorphic mixture of Form A and Form B oflinagliptin, the process comprising recrystallizing linagliptin in asolvent selected from the group consisting of C₁-C₅ alcohol, a C₂-C₉ester, a C₃-C₉ ketone, a C₃-C₅ carbonate, nitriles, hydrocarbon solventsand halogenated derivatives thereof, ethers, acetic acid,dimethylformamide (DMF), dimethylacetamide (DMAC), N-methylpyrrolidine,formamide, N-methylacetamide, N-methylformamide,dimethylsulfoxide(DMSO), ethylformate, sulfonate,N,N-dimethylpropionamide, nitromethane, nitrobenzene, andhexamethylphosphoramide, and mixtures thereof and mixtures of saidorganic solvents and water.

The C₁-C₅ alcohol may be selected from the group consisting of methanol,ethanol, n-propanol, isopropanol, n-butanol, isobutanol, 2-butanol andthe like. The C₂-C₉ ester may be selected from the group consisting ofmethyl acetate, ethyl acetate, isopropyl acetate, isobutyl acetate,n-butyl acetate, t-butyl acetate and the like. The C₃-C₉ ketone may beselected from the group consisting of acetone, 2-butanone, methylethylketone, ethylmethylketone, isopropylmethylketone, methyl isobutyl ketoneand the like. The C₃-C₅ carbonate may be selected from the groupconsisting of dimethyl carbonate, diethyl carbonate and the like;nitriles such as acetonitrile, propionitrile and the like.

The hydrocarbon solvents and halogenated derivatives may be selectedfrom the group consisting of pentane, hexane, heptane, cyclohexane,petroleum ether, toluene, benzene, cycloheptane, methylcyclohexane,ethylbenzene, m-, o-, or p-xylene, octane, indane, nonane,dichloromethane (MDC), chloroform, carbon tetrachloride,1,2-dichloroethane and the like. The ethers may be selected from thegroup consisting of diethyl ether, dimethyl ether, dimethoxymethane,dimethoxypropane, isopropyl ether, di-isopropyl ether, methyl t-butylether, tetrahydrofuran (THF), dioxane, furan, ethylene glycol dimethylether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether,diethylene glycol diethyl ether, anisole and the like.

In yet another embodiment, the present invention provides a process forthe preparation of a mixture polymorphic Form A and B of linagliptin,the process comprising recrystallizing linagliptin in a solvent selectedfrom the group consisting of C₁-C₅ alcohol, ethers, esters,dimethylsulfoxide and mixtures thereof or their mixture with water.

In yet another embodiment, the present invention provides a process forthe preparation of a mixture polymorphic Form A and B of linagliptin,the process comprising recrystallizing linagliptin in ethyl acetate.

In yet another embodiment, the present invention provides a process forthe preparation of a mixture polymorphic Form A and B of linagliptin,the process comprising recrystallizing linagliptin in isopropyl alcohol.

In yet another embodiment, the present invention provides a process forthe preparation of a mixture polymorphic Form A and B of linagliptin,the process comprising recrystallizing linagliptin in dimethylsulfoxideand water mixture.

In yet another embodiment, the present invention provides a process forthe preparation of linagliptin, the process comprising recrystallizinglinagliptin from a mixture of methylene dichloride and methyl t-butylether.

In yet another embodiment, the present invention provides a process forthe preparation of a mixture polymorphic Form A and B of linagliptin,the process comprising recrystallizing linagliptin from a mixture ofmethylene dichloride and methyl t-butyl ether.

In yet another embodiment, the present invention provides a process forthe preparation of a mixture of polymorphic Form A and B of linagliptin,the process comprising recrystallizing linagliptin from a mixture ofmethanol and methyl t-butyl ether.

In one embodiment the present invention provides a process for thepreparation of a mixture of polymorphic Form A and B of linagliptin, theprocess comprising heating linagliptin in methanol at reflux temperatureadding methyl t-butyl ether at reflux temperature and stirring thereaction mass at refluxing temperature for a period of about 30 mins to1 hour and cooling the reaction mixture slowly at room temperature.

In one embodiment the present invention provides a process for thepreparation of a mixture of polymorphic Form A and B of linagliptin, theprocess comprising heating linagliptin in methanol at reflux temperatureadding methyl t-butyl ether at reflux temperature and stirring thereaction mass at refluxing temperature for a period of about 30 mins to1 hour and cooling the reaction mixture slowly at room temperature andseeding the reaction mixture with a mixture of polymorphic form A and Bto isolate a mixture of polymorphic Form A and B of linagliptin.

In one embodiment the present invention provides a process for thepreparation of a mixture of polymorphic Form A and B of linagliptin, theprocess comprising heating linagliptin in methanol at reflux temperatureadding methyl t-butyl ether at reflux temperature and stirring thereaction mass at refluxing temperature for a period of about 30 mins to1 hour and cooling the reaction mixture slowly at room temperature andseeding the reaction mixture with polymorphic B to isolate a mixture ofpolymorphic Form A and B of linagliptin.

In yet another embodiment, the present invention provides a process forthe preparation of polymorphic Form C of linagliptin, the processcomprising recrystallizing linagliptin from a mixture of methanol andmethyl t-butyl ether.

In one embodiment the present invention provides a process for thepreparation of polymorphic Form C of linagliptin, the process comprisingheating linagliptin in methanol at reflux temperature, cooling thereaction mass to a temperature in the range of about 0° C. to about 15°C. and adding methyl t-butyl ether and stirring the reaction mass.

The following examples are provided to enable one skilled in the art topractice the invention and are merely illustrative of the invention. Theexamples should not be read as limiting the scope of the invention asdefined in the features and advantages.

EXAMPLES Example 1 Preparation of (R)-N-piperidin-3-ylacetamideDibenzoyl Tartarate Salt

(a) Preparation of N-(pyridin-3-yl)-acetamide: In a RBF 500 ml oftetrahydrofuran (THF), 100 gm of 3-amino pyridine were charged undernitrogen atmosphere. Added 130 gm of acetic anhydride at about 0-5° andmaintained the reaction mass for about 17 hr at room temperature tocomplete the reaction. Distilled off the THF below about 45° C. undervacuum. Charged 2000 ml of diisopropylethylamine and heated the reactionmass to about 50° C. for about 30 min. Cooled the reaction mass to roomtemperature and filtered the product and then washed with 200 ml DIPEA.Dried the product at about 45-50°.

(b) Preparation of N-piperidin-3-yl-acetamide: In an autoclave 500 ml ofacetic acid, 100 gm of N-(pyridin-3-yl)-acetamide and 20 gm of 10% Pd/Cwere charged. 10 kg hydrogen pressure was applied to the reaction massand the temperature was raised to about 80° C. Maintained the reactionmass for about 5.0 hrs and after completion of the reaction, thereaction mass was filtered through Hyflobed. Acetic acid was distilledoff under vacuum below about 55° C. to get an oily mass. The oily masswas dissolved in 1000 ml of methylene dichloride and the pH adjusted toabout 10-12 by using sodium hydroxide solution. The salt was filteredand washed with 300 ml methylene dichloride. Distilled off the methylenedichloride under vacuum below 35° C. to get an oil. Wt of Oil 95.0 gm

(c) Preparation of (R)-N-piperidin-3-ylacetamide Dibenzoyl tartaratesalt: In a RBF charged 500 ml of Methanol, 50 gm ofN-piperidin-3-ylacetamide & 138 gm of L (+)-Dibenzoyl tartaric acid. Thereaction was maintained for about 90 mins at room temperature and thenheated to reflux. The reaction mass was maintained for about an hour atreflux and then cooled and maintained at room temperature for about 12.0hours. Then, the product was filtered and washed with 100 ml methanol.Again charged the obtained wet cake in 800 ml methanol, heated to refluxand maintained reaction mass for 1.0 hr to get a clear solution. Cooledthe reaction mass to room temperature and maintained for 12.0 hrs. Theproduct was filtered and washed with 100 ml methanol. The product wasdried at about 45-50° C. under vacuum. Unwanted S-isomer NMT 1.5% DryWt-20. Gm.

Example 2 Preparation of R-3-(4-Methylphthalimido)-piperidine

(a) Preparation of 3-Aminopiperdine dihydrochloride: In a clean roundbottom flask, 400 ml of Conc HCl and 100 gm of N-piperidin-3-ylacetamide(prepared in Ex 1 b) were charged & refluxed for 4 hours. The reactionmass was concentrated to get thick oil. 500 ml ethanol was added to theoil & stirred at room temperature to get solid. Dry wt 100 gms

(b) Preparation of 3-(4-Methylphthalimido)piperidine In a clean roundbottom flask, 30 ml acetic acid, 10 gms 3-aminopiperidinedihydrochloride & 14 gms 4-methylphthalic anhydride were charged. Thereaction mass was refluxed for 1 hour & then cooled to 60° C. Thereaction mass was concentrated to get the oily mass. 100 ml ethanol wasadded to reaction mass. The reaction mass was heated to 78-80° C. to getuniform slurry. The reaction mass was cooled to room temp & filtered toget the titled compound. Dry wt 8.5 gms.

(c) Resolution of 4-Methylphthalimido-3-piperidine

Method 1: In a clean round bottom flask, 1.0 gms3-(4-Methylphthalimido)piperidine & 5 ml acetic acid were charged. Asolution of D(−)-tartaric acid in 5 ml ethanol was added to the reactionmass at about 85-90° C. & stirred for 30 minutes. The reaction mass wascooled to RT & filtered & washed with 2 ml ethanol to obtain a solid.The solid was taken in water and the pH was adjusted to 8-10 usingliquid ammonia. Methylene dichloride was added to the aqueous layer. Theorganic layer was separated and the product isolated from the organiclayer.

Method 2: In a clean round bottom flask, 1.0 gms3-(4-Methylphthalimido)piperidine & 10 ml ethyl acetate were charged. Asolution of dibenzoyl tartaric acid in 5 ml ethyl acetate was added tothe reaction mass at 78-82° C. & stirred for 30 minutes. The reactionmass was cooled to RT & filtered & washed with 2 ml ethyl acetate. 10 mlethyl acetate was added to the obtained wet cake & heated at reflux forabout 1.0 hr to get uniform slurry. The reaction mass was cooled to RT &maintained for 12.0 hrs. The product was filtered & washed with 2 mlethyl acetate. The solid was taken in water and the pH was adjusted to8-10 using sodium hydroxide. Methylene dichloride was added to theaqueous layer. The organic layer was separated and the product isolatedfrom the organic layer

Example 3 Preparation of 3-(R)-4-Methylphthalimido)piperidine

(a) Preparation of 3-(R)-Aminopiperidine dihydrochloride: In a cleanround bottom flask, 400 ml of Conc HCl and 100 gm ofN-piperidin-3-(R)-ylacetamide dibenzoyl tartarate salt (prepared in Ex 1c) were charged & refluxed for 4 hours. The reaction mass wasconcentrated to get thick oil. Added 500 ml ethanol to the oil & stirredat RT to get solid. Dry wt 100 gms

(b) 3-(R)-(4-Methylphthalimido)piperidine: In a clean round bottomflask, 30 ml acetic acid, 10 gms 3-(R)-aminopiperidine dihydrochloride &14 gms 4-methylphthalic anhydride were charged. The reaction mass wasrefluxed for 1 hour & then cooled to 60° C. The reaction mass wasconcentrated to get the oily mass. 100 ml ethanol was added to reactionmass. The reaction mass was heated to 78-80° C. to get uniform slurry.The reaction mass was cooled to room temperature & filtered to get thetitled compound.

Example 4 Preparation of1-[(4-Methylquinazolin-2-yl)methyl]-3-methyl-7-(2-butin-1-yl)-8-(3-(R)-4-methylphthalimidopiperidin-1-yl-xanthine

In a clean round bottom flask 5 gms of1-[4-methylquinazolin-2yl)-methyl]-3-methyl-7-(2-but-1-nyl)-8-bromoxanthine,4.0 gms of (R-)3-(4-methylphthalimido)-piperidine, 0.9 gms of potassiumcarbonate & 50 ml of dimethylformamide were charged. The reaction masswas maintained at about 80° C. for about 12 hrs. The reaction mass wascooled to about room temperature and 100 ml water was added. Then, theproduct was extracted with 50 ml methylene dichloride. The methylenedichloride layer was concentrated and the product was isolated in methyltertiary butyl ether. Dry wt 4 gms.

Example 5 Preparation of1-[(4-Methylquinazolin-2-yl)methyl]-3-methyl-7-(2-butin-1-yl)-8-(3-(R)-4-methylphthalimidopiperidin-1-yl)-xanthine

In a clean round bottom flask, 1 gm of1-[4-methylquinazolin-2yl)-methyl]-3-methyl-7-(2-but-1-nyl)-8-bromoxanthine,1.3 gms of 3-(R)-(4-methylphthalimido)-piperidine tartrate salt, 0.5 gmsof potassium carbonate & 10 ml of dimethylformamide were charged. Thereaction mass was maintained at about 80° C. for 12 hrs. The reactionmass was cooled to about room temperature & 20 ml water was added & theproduct extracted with 20 ml methylene dichloride. The methylenedichloride layer was concentrated & the product was isolated in methyltertiary butyl ether. Dry wt 1.09 gms.

Example 6 Preparation of Linagliptin

In a RBF 1 ml of toluene, 100 mg of1-[(4-Methylquinazolin-2-yl)methyl]-3-methyl-7-(2-butin-1-yl)-8-(3-(R)-4-methylphthalimidopiperidin-1-yl)-xanthine,0.1 ml of ethanolamine were charged, the temperature was raised-to about100-110° C. and the reaction mass was maintained for about 3 hours tocomplete the reaction. After the completion of the reaction, thereaction mass was cooled to about 80° C. The aqueous and oil layers wereseparated. The aqueous layer was extracted again with 1 ml of toluene.The organic layers were combined and washed with 2 ml of water at about80° C. The organic layer was concentrated under vacuum to get an oilymass. Added 2 ml water to the oily mass and adjusted the pH to about 2-3using aq. HCl. The aqueous layer was washed with methylene dichloride(MDC). The pH of aqueous layer was adjusted to about 10-12 using 5% aqNaOH solution. The product was extracted in MDC and worked up by eitherof the methods (a), (b) or (c) listed below .

(a) MDC layer was concentrated & product was isolated by methanol. Drywt 50 mg. HPLC purity>99.0%. (b) MDC layer was concentrated & productwas dissolved in a mixture of 5 ml acetone & 5 ml ethyl acetate at40-45° C. Reaction mass cooled to RT & filtered. Wet cake was washedwith 2 ml mixture of ethyl acetate & acetone. Dry wt 40 mg. HPLCpurity>99.0%. (c) MDC layer was concentrated & product was dissolved in10 ml IPA at 40-45° C. Reaction mass cooled to RT & filtered. Wet cakewas washed with 2 ml IPA. Dry wt 60 mg. HPLC purity>99.0%.

Example 7 Preparation of Linagliptin

In a clean round bottom flask, 9 ml of ethanol, 90 mg of1-[(4-Methylquinazolin-2-yl)methyl]-3-methyl-7-(2-butin-1-yl)-xanthine &0.9 ml of hydrazine hydrate were charged. The temperature of thereaction mass was raised to 78-80° C. & the reaction mass was maintainedfor 3 hours. The reaction mass was cooled to 50° C. & ethanol wasdistilled off. 9 ml methylene dichloride was added to the obtainedresidue & stirred at RT to get the solid. Undesired solid was filtered.The filtrate was concentrated & 9 ml methyl tert butyl ether was addedto the residue to get the solid Linagliptin. Reaction mass was stirredat RT & filtered. Wet cake was washed with 2 ml IPA. Dry wt 45 mg

Example 8 Crystallization of Linagliptin

0.50 gm of Linagliptin and 2.5 ml of ethanol was charged into a cleanand dried round bottom flask and refluxed for about 30 min. Subsequentlythe solution was slowly cooled to about 20° C. No precipitate wasobserved at about 20° C. Further, the solution was cooled to below 10°C. and the precipitation was observed. 5.0 ml of MTBE added and stirredfor 60 min below 10° C. The mixture is filtered and dried under vacuumat ambient temperature.

Example 9 Crystallization of Linagliptin

2.00 gm of Linagliptin and 10.0 ml of ethanol was charged in to a cleanand dried round bottom flask and refluxed for about 1.5 min.Subsequently the solution is slowly cooled to about 25° C. Further, thesolution was cooled to below 0° C. and maintained for about an hour andprecipitation was observed. Thereafter, 20.0 ml of MTBE added andstirred for about 60 min below about 10° C. The mixture was filtered anddried under reduced pressure below 10° C.

Example 10 Crystallization of Linagliptin

0.10 gm of Linagliptin and 0.30 ml of dimethylsulfoxide (DMSO) wascharged in to a clean and dried round bottom flask and warmed for about5 min to get a clear solution. The mixture was quenched in 25 volume ofwater and stirred overnight. Reaction mixture was filtered and driedunder reduced pressure ambient temperature.

Example 11 Crystallization of Linagliptin

0.10 gm of Linagliptin and 10.0 ml of isopropanol was charged into aclean and dried round bottom flask and refluxed for about 15 min.Subsequently the solution was slowly cooled to about 25° C. Further, thesolution was stirred and maintained for about 2 hr and precipitation wasobserved. The mixture was filtered and dried under reduced pressure atabout 25-30° C. overnight.

Example 12 Crystallization of Linagliptin

1 g of linagliptin was recrystallized from a mixture of 5 ml of ethylacetate and 5 ml of acetone.

Example 13 Preparation of 3-(R)-4-Methylphthalimido)piperidine

In a clean round bottom flask, 100 ml acetic acid, 50 gms3-(R)-aminopiperidine dihydrochloride & 56.5 gms of 4-methylphthalicanhydride were charged. The reaction mass was refluxed & then cooled to25-30° C. Acetone was added to the reaction mass & obtained solid wasfiltered. Acetone was added to the solid obtained & refluxed to getuniform slurry. The reaction mass was cooled to 25-30° C. & filtered.Wet wt 70 gms. In another round-bottom flask, methylene dichloride, wetcake and water were charged. The reaction mass was basified & layerswere separated. The organic layer was washed with water & concentratedupto half volume. Diisopropyl ether was added to the reaction mass toobtain the product Dry wt 40 gms,HPLC purity=85%

Example 14 Preparation of 3-(R)-4-Methylphthalimido)piperidine

In a clean round bottom flask, 1000 ml methanol and 200 gm3-(R)-aminopiperidine dihydrochloride were charged. Cooled the reactionmass to 0-10° C. and added 1850 ml 2.5% methanolic NaOH solution slowlyat 0-10° C. Stirred and filtered the inorganic solid, distilled outclear filtrate under vacuum below 45° C. Added 400 ml acetic acid andcooled the reaction mass to room temperature, added 226.1 gm4-methylphthalic anhydride. Reaction mass was refluxed & then cooled to25-30° C. Acetone was added to the reaction mass & obtained solid wasfiltered. Acetone was again added to the solid obtained & refluxed toget uniform slurry. The reaction mass was cooled to 25-30° C. &filtered. Dry wt: 280 gms. In another round bottom flask, above driedsolid material, methylene dichloride and water were charged. Thereaction mass was basified & layers were separated. The organic layerwas washed with water & concentrated upto half volume. Diisopropyl etherwas added to the reaction mass to obtain the product

Dry wt: 175 gms,

HPLC purity=96.16%

Example 15 Preparation of1-[4-Methylquinazolin-2yl-methyl]-3-methyl-7-(2-but-1-nyl)-8-bromoxanthine

In a round bottom flask, 140 ml DMF, 20 gm of8-bromo-7-but-2-yn-1-yl-methyl-3,7-dihydro-1H-purine-2,6-dione and 15.67gm of 2-(chloromethyl)-4-methyl-1,2-dihydroquinazoline were charged. 14gm potassium carbonate was added to the reaction mass and heated to95-100° C. for 3 hours. The reaction mass was cooled to 0-10° C. & added100 ml water. The reaction mass was allowed to come to 25-30° C. Thesolid obtained was filtered & the slurry was washed with water. Theobtained solid was purified in ethyl acetate to get the product. Dry wt25 gms, HPLC purity=98%

Example 16 Preparation of1-[(4-Methylquinazolin-2-yl)methyl]-3-methyl-7-(2-butin-1-yl)-8-(3-(R)-4-methylphthalimidopiperidin-1-yl)-xanthine

In a clean round bottom flask 40 ml N-Methyl-2-Pyrrolidone (NMP), 10 gm8-bromo-7-(but-2-yn-1-yl)-3-methyl-1-[(4-methylquinazolin-2-yl)methyl]-3,7-dihydro-1H-purine-2,6-dioneand 8.1 gm 4-methyl-3-(R)-pthalimidopiperidine were charged. Thetemperature of the reaction mass was raised to 80-85° C. & 10 mldiisopropylamine was added. The reaction mass was heated to 100-105° C.& maintained at this temp to complete the reaction. On completion ofreaction, reaction mass was cooled to 35-40° C. & methanol was added.The reaction mass was further cooled to 25-30° C. & filtered. Obtainedwet material was again purified in methanol to get the product. Dry wt10 gms, HPLC purity=97%

Example 17 Preparation of1-[(4-Methylquinazolin-2-yl)methyl]-3-methyl-7-(2-butin-1-yl)-8-(3-(R)-4-methylphthalimidopiperidin-1-yl)xanthine

In a clean round bottom flask 680 ml N-Methyl-2-Pyrrolidone (NMP), 170gm8-bromo-7-(but-2-yn-1-yl)-3-methyl-1-[(4-methylquinazolin-2-yl)methyl]-3,7-dihydro-1H-purine-2,6-dioneand 138 gm 4-methyl-3-(R)-pthalimidopiperidine were charged. Thetemperature of the reaction mass was raised to 80-85° C. & 170 mldiisopropylamine was added. The reaction mass was heated to 100-105° C.& maintained at this temp. On completion of reaction, the reaction masswas cooled to 35-40° C. & methanol was added. The reaction mass wasfurther cooled to 25-30° C. & filtered. The wet material obtained wasagain slurried in methanol to get the crude product, wet wt: 287 gm. Inanother round bottom flask, 595 ml methanol, 255 ml MDC and crude wetcake were charged. The reaction mass was heated to reflux and thencooled to room temperature. The solid obtained was filtered and washedwith methanol to get the pure product. Dry wt: 162 gms, HPLCpurity=98.77%

Example 18 Preparation of Linagliptin Crude

In a clean round bottom flask, 10 gm of1-[(4-Methylquinazolin-2-yl)methyl]-3-methyl-7-(2-butin-1-yl)-8-(3(R)-4-methylphthalimidopiperidine-yl)-xanthineand 100 ml of toluene were charged. 10 ml of ethanolamine was added tothe reaction mass and heated to 90-95° C. to complete the reaction. Thereaction mass was cooled to 80° C. and the layers were separated. Theorganic phase was distilled under vacuum to get crude linagliptin. Drywt: 7.50 gm HPLC purity: 97.95% Impurity X: 0.69%

Example 19 Preparation of Linagliptin Crude

In a clean round bottom flask, 10 gm of1-[(4-Methylquinazolin-2yl)methyl]-3-methyl-7-(2-butin-1yl)-8-(3(R)-4-methylphthalimidopiperidine-yl)-xanthine and 100 ml of toluene were charged,10 ml of ethanolamine was added to the reaction mass and heated to75-80° C. to complete the reaction. The reaction mass was cooled to50-55° C. Water was added to reaction mass & layers were separated.Organic phase was distilled under vacuum to get Linagliptin crude. Drywt: 7.50 gm

Example 20 Preparation of Linagliptin

In a clean round bottom flask, 10.0 gms of 1-[(4-Methylquinazolin-2yl)methyl]-3-methyl-7-(2-butin-1yl)-8-(3(R)-4-methylphthalimidopiperidine-yl)-xanthine and 50 ml ethanolamine were charged.The reaction mass was heated to 90-100° C. for 1 hr and cooled to roomtemperature. 100 ml water was added and the solid was filtered. 150 mlof toluene was added and completely distilled out under vacuum at 45-50°C. to get pale yellow solid. Dry wt: 6.0 gm.

Yield: 78.94%, (molar yield) Purity: 98.83%.

Example 21 Preparation of Linagliptin Dibenzoyl-D-tartaric Acid Salt

In a clean round bottom flask, 7.5 gm of crude linagliptin and 100 mlmethanol were charged. A solution of 5.81 gm Di-benzoyl-D-Tartaric acidin 100 ml methanol was added at 60° C. and the reaction mass was stirredfor 1.0 hr. The reaction mass was cooled to room temperature and theobtained salt was filtered and washed with 20 ml methanol. Dry wt: 12.0gm HPLC purity: 99.54%, Impurity X: 0.20%

Example 22 Purification of Linagliptin Dibenzoyl-D-tartaric Acid Salt

In a clean round bottom flask, 12 gm of Linagliptin dibenzoyl-D-tartaricacid salt and 120 ml isopropanol were charged. The reaction mass washeated to reflux & maintained for 1.0 hr at reflux. The reaction masswas cooled to room temperature and stirred for 1.0 hr. The solid wasfiltered and washed with isopropanol. Dry Wt: 11.70 gm, HPLC purity:99.63%, Impurity X: 0.08%.

¹H NMR (400 MHz) of Linagliptin dibenzoyl-D-tartaric acid salt:1.03-1.04 (d, 2H), 1.57 (m, 2H), 1.76-1.77 (incompletely resolved, s,3H,) superimposed with 1.77 (m, 1H), 1.93 (m, 1H), 2.88 (s, 3H),3.0-3.12 (m, 2H), 3.32-3.33 (m, 1H), 3.46-3.49, (dd, 1H), 3.65-3.67 (dd,1H), 4.83-4.95(m, 2H), 5.33 (s, 2H), 5.66 (s, 2H), 7.47-8-28 (4+10H).

XRD Table of Linagliptin Dibenzoyl-D-tartaric Acid Salt

Pos d spacing Rel. Int Pos Rel. Int [°2θ] [Å] % [°2θ] d spacing % 2.0842.37 2.24 12.75 6.94 30.78 6.35 13.91 100.00 13.29 6.66 14.43 7.6211.59 83.66 14.05 6.30 67.57 9.34 9.47 16.61 14.46 6.13 21.19 10.94 8.0927.27 15.05 5.89 26.20 11.35 7.80 9.39 15.84 5.60 7.53 11.77 7.52 14.8016.56 5.35 8.08 12.14 7.29 10.99Differential Scanning Calorimetric (DSC) thermogram having an endothermpeak at about 233±0.2° C. The TGA shows a weight loss of 0.6% upto 150°C. over a range of 0-250° C.

Example 23 Preparation of Linagliptin

In a clean round bottom flask, 150 gms Linagliptin dibenzoyl-D-tartaricacid salt, 1500 ml water and 1500 ml MDC were charged. The reaction masswas basified with 5% aq. NaOH solution and the layers were separated.The organic layer was washed with water and distilled out under vacuumbelow 40° C. to get pale yellow semisolid. 150 ml methanol was added andheated to 60-65° C. to get a clear solution. The reaction mass wascooled to 50-55° C. and 1200 ml methyl tert-butyl ether was added slowlyat this temperature. The slurry obtained was stirred for 30 min at50-55° C. and then cooled to room temperature, filtered and washed with150 ml methyl tert-butyl ether to obtain a mixture of Form A and Form Bof Linagliptin. Dry wt: 80 gm Related substance by HPLC: Compound offormula III: not detected, Compound of formula IIA1: not detected; HPLCPurity: 99.85%; S-isomer by HPLC: 0.02%

Example 24 Preparation of Linagliptin

In a clean round bottom flask, 10 gm of Linagliptin dibenzoyl-D-tartaricacid salt and 100 ml methylene dichloride were charged. 100 ml water wasadded and pH was adjusted to 8-10 by adding 5% Aq. NaOH. The reactionmass was stirred at room temperature for 30 min. and the layers wereseparated. The organic layer was distilled under vacuum and purelinagliptin was isolated from a 120 ml mixture of methylene dichlorideand methyl tert butyl ether. Dry Wt: 5.50 gm HPLC purity: 99.64%,Impurity X: 0.06% Chiral Purity: Unwanted isomer:8-[3(S)-Aminopiperidin-1-yl]-7-(2-butynyl)-3-methyl-1-(4-methylquinazolin-2-ylmethyl)xanthine,NMT 0.02%

Example 25 Preparation of Form-C of Linagliptin

In a clean round bottom flask, 2.0 gms Linagliptin and 20 ml methanolwere charged. The reaction mass was heated to 50-55° C. to get a clearsolution. Reaction mass was cooled to 5-10° C. and added 20 ml methyltert-butyl ether slowly at 5-10° C. Stirred for 30 min at 5-10° C. andfiltered, washed with 4 ml methyl tert-butyl ether. Dry wt: 1.6 gm

Example 26 Preparation of Form-C of Linagliptin

In a clean round bottom flask, 2.0 gms Linagliptin and 20 ml methanolwere charged. The reaction mass was heated to 50-55° C. to get clearsolution. Reaction mass was cooled to 5-10° C. and added 40 ml methyltert-butyl ether slowly at 5-10° C. Stirred for 30 min at 5-10° C. andfiltered, washed with 4 ml methyl tert-butyl ether. Dry wt: 1.6 gm

Example 27 Preparation of Form-A of Linagliptin

In a clean round bottom flask, 10 gms Linagliptin dibenzoyl-D-tartaricacid salt, 100 ml water and 100 ml MDC were charged. The reaction masswas basified with 5% aq. NaOH solution and layers were separated.Organic layer was washed with water and distilled out under vacuum at40° C. to get pale yellow semisolid. 20 ml ethanol was added and heatedto reflux to get a clear solution. Reaction mass was cooled to 55-60° C.and added 40 ml methyl tert-butyl ether. Stirred for 30 min at 55-60° C.and cooled to room temperature, filtered and washed with 20 ml methyltert-butyl ether. Dry wt: 5.30 gm HPLC purity: 99.66%

Example 28 Preparation of Linagliptin in Toluene and Ethanolamine Using1-[(4-Methylquinazolin-2yl)methyl]-3-methyl-7-(2-butin-1yl)-8-(3(R)-4-methylphthamidopiperidine-yl)-xanthine

In a clean round bottom flask, 10.0 gms of 1-[(4-Methylquinazolin-2yl)methyl]-3-methyl-7-(2-butin-1yl)-8-(3(R)-4-methylphthalimidopiperidine-yl)-xanthine and 100 ml toluene were charged. 11ml of ethanolamine was added and the reaction mass was heated to100-105° C. for 3 hrs. The reaction mass was cooled to 80-85° C. and thelayers were separated. The organic layer was washed with 100 ml waterand distilled out the organic layer completely under vacuum at 45-50° toget pale yellow solid. Yield: 90%, Purity: 97.49%.

Comparative Example Preparation of Linagliptin in Toluene andEthanolamine Using 1-[(4-methylquinazolin-2yl)methyl]-3-methyl-7-(2-butin-1yl)-8-(3(R)-phthalmidopiperidine-yl)-xanthineIntermediate

In a clean round bottom flask, 5.0 gms of 1-[(4-Methylquinazolin-2yl)methyl]-3-methyl-7-(2-butin-1yl)-8-(3(R)-phthalimidopiperidine-yl)-xanthineand 50 ml toluene were charged. 10 ml ethanolamine was added and thereaction mass was heated to 100-105° C. for 2 hrs. The reaction mass wascooled to 80° C. and the layers were separated. The organic layer wasdistilled out completely under vacuum at 45-50° C. and the productisolated in 25 ml methyl tert butyl ether to get pale yellow solid. Drywt: 1.80 gm. Yield: 46.15%, Purity: 94.98%.

It was observed that the linagliptin obtained by using unsubstitutedphthalimidopiperidine as exemplified in the comparative example has alower purity and the yield of linagliptin obtained is very low ascompared to the linagliptin obtained by the process of the presentinvention using substituted phthalimidopiperidine compound of formulaIIA1 (example 28).

1-10. (canceled)
 11. Linagliptin dibenzoyl-D-tartaric acid salt.
 12. Thelinagliptin dibenzoyl-D-tartaric acid salt of claim 11 in crystallineform characterized by an XRD pattern having peak reflections at about6.35, 7.52, 14.05±0.2 degrees 2 theta. 13.-16. (canceled)
 17. Thecrystalline linagliptin dibenzoyl-D-tartaric acid salt of claim 11characterized by a ¹H NMR spectrum having peaks at δ 1.03-1.04, 1.57,1.76-1.77, 1.93, 2.88, 3.0-3.12, 3.32-3.33, 3.46-3.49, 3.65-3.67,4.83-4.95, 5.33, 5.66, 7.47-8-28.
 18. The crystalline linagliptindibenzoyl-D-tartaric acid salt of claim 11, characterized byDifferential Scanning Calorimetric (DSC) thermogram having an endothermpeak at about 2.33±0.2° C.
 19. A process for the preparation oflinagliptin dibenzoyl-D-tartaric acid salt comprising reactinglinagliptin with dibenzoyl-D-tartaric acid.